tbuckley/cabot-search huggingface dataset:
Abstract 1049: Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in advanced breast cancer
Authors: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia
Journal: Cancer Research (2023)

Abstract Introduction: Breast cancer is the most common malignancy worldwide in females, with more than 2.26 million new cases and 680 thousand of deaths in 2020. Advanced breast cancer is characterized by complicated genomic landscape and requires comprehensive genomic profiling. However, tissue biopsy is hard to get in patients with recurrent metastasis. Meanwhile, limited studies have been reported to use liquid biopsy and were not capable of reporting gene copy number loss. Here we reported a comprehensive genomic profiling study in advanced breast cancer patients using liquid biopsy. Methods: The prospective study is part of the Predicine’s Phoenix Program, a global molecular biomarkers screening program in multiple solid tumors. Currently, the study enrolled 220 advanced breast cancer patients from 8 centers in China, who were naïve to the 1st line treatment. 10ml of blood was collected from each patient and delivered to a central lab for ctDNA analysis. The study applied PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients. Results: The study identified 793 somatic mutations and 283 copy number variants among blood samples from 220 patients. The most common altered genes were TP53(101/220, 46%), PIK3CA(77/220, 35%), BRCA2(37/352, 17%), PTEN(26/220, 12%), and ATM(24/220, 11%). Gene copy number gain incidents were identified on MYC(n=28), AKT3(n=23), FGFR1(n=18), and PIK3CA(n=16), etc. The study also reported gene copy number loss incidents through liquid biopsy, such as CDKN2A(n=17), BRCA1(n=12), TP53(n=11), RB1(n=11), BRCA2(n=10), PTEN(n=9), and ATM(n=8). Conclusions: This study revealed the comprehensive mutational landscape of advanced breast cancer patients through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies. Citation Format: Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia. Liquid biopsy-based comprehensive genomic profiling reveal mutational landscape in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1049.
Abstract 2078: VALIS: Virtual Alignment of pathoLogy Image Series for multi-gigapixel whole slide images
Authors: Chandler Dean Gatenbee, Ann-Marie Baker, Sandhya Prabhakaran, Mark Robertson-Tessi, Trevor Graham, Alexander R. Anderson
Journal: Cancer Research (2023)

Abstract Interest in spatial omics is on the rise, but generation of highly multiplexed images used in many spatial analyses remains challenging, due to cost, expertise, methodical constraints, and/or access to technology. An alternative to performing highly multiplexed staining is to register collections of whole slide images (WSI), creating a collection of aligned images that can undergo spatial analyses. However, registration of WSI is two part problem, with the first being the alignment itself, and the second being the application of the transformations to huge multi-gigapixel images. To address both challenges, we have developed the Virtual Alignment of pathoLogy Image Series (VALIS) software, which enables one to rapidly and easily generate highly multiplexed images by aligning (registering) any number of multi-gigapixel whole slide images (WSI) stained using immunohistochemistry (IHC) and/or immunofluorescence (IF). Benchmarking using the publicly available 2019 ANHIR and 2022 ACROBAT Grand Challenge datasets indicates that VALIS provides state of the art accuracy, being one of the most accurate publicly available methods in the ANHIR challenge, and the most accurate opensource method in the ACROBAT challenge. VALIS is able to read, register, and save multi-gigapixel images as ome.tiff, thereby addressing the second challenge. In addition to the benchmarking datasets, the generalizability of VALIS has been tested with 273 IHC samples and 340 IF samples, each of which contained between 2-69 images per sample. In total, VALIS has therefore been tested with 5,138 images. The registered WSI tend to have low error and are completed within a matter of minutes. VALIS is written in Python, requires only few lines of code for execution, is readily available and fully documented. VALIS therefore provides a free, opensource, flexible, scalable, robust, and easy to use pipeline for rigid and non-rigid registration of multi-gigapixel WSI, facilitating spatial analyses of prospective and existing datasets,breathing new life into the countless collections of brightfield and immunofluorescence images. Citation Format: Chandler Dean Gatenbee, Ann-Marie Baker, Sandhya Prabhakaran, Mark Robertson-Tessi, Trevor Graham, Alexander R. Anderson. VALIS: Virtual Alignment of pathoLogy Image Series for multi-gigapixel whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2078.
Abstract 1366: HMGB1 localization and its effect on the immune response in the lung tumor microenvironment
Authors: Kisa Jafri, Nicole M. Andre, Glenn E. Simmons
Journal: Cancer Research (2023)

Abstract Lung adenocarcinoma is the leading cause of cancer mortality. High Mobility Group Box 1 (HMGB1) is a master regulator of innate immunity that is elevated in lung cancer tissues. Furthermore, HMGB1 has been previously demonstrated to suppress functional anti-tumor immune responses in this context. However, beyond demonstrating that HMGB1 is elevated and modulates inflammation, studies to date have not comprehensively investigated the influence of HMGB1 on the immune response to lung cancer. HMGB1 contributes to PD-L1 expression in melanoma and promotes secretion of inhibitory cytokines TGF-α and IL-10, which have roles in the differentiation of regulatory T cells. Therefore, HMGB1 sits atop an immunomodulatory signaling cascade in the tumor microenvironment. While treatment of lung cancers with immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1) has had success, there are limitations. One major limitation is the failure of patients with advanced or refractory disease to generate a strong anti-tumor immune response. Recently, we have identified HMGB1 as a protein that is functionally dependent on monounsaturated fatty acid (MUFA) availability. Utilizing a combination of molecular assays and 3-dimensional cultures, we now show that HMGB1 is sequestered intracellularly, rather than being secreted extracellularly in a MUFA-dependent fashion. We hypothesized that MUFAs promote an anti-tumor immune response via modulating HMGB1 release from cancer cells. Thus, by restricting extracellular HMGB1 levels, HMGB1-responsive proinflammatory/tumor signaling pathways (e.g., NF-kB) are suppressed. Taken together, these observations suggest a novel approach to decreasing maladaptive immune and inflammatory signaling from innate immune cells. Exploiting the MUFA/HMGB1 signaling axis could be a novel approach to improve the efficacy of therapies in populations that are not currently benefiting from current strategies for eliminating tumors. Citation Format: Kisa Jafri, Nicole M. Andre, Glenn E. Simmons. HMGB1 localization and its effect on the immune response in the lung tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1366.
Abstract 6414: Concomitant anti-tumor immunity and checkpoint blockade responses are restored by depletion of CD62L expressing cells
Authors: Brianna Burke, Lourdes Plaza-Rojas, Cynthia Perez, Elena Kostenko, Anna Austin, Justin Boucher, Kushal Prajapati, Michael Delos Reyes, Christine Chung, Jose-Alejandro Guevara-Patino
Journal: Cancer Research (2023)

Abstract Studies have shown the importance of CD62L in leukocyte trafficking. However, the significance of CD62L-expressing cells in concomitant anti-tumor immunity has not been investigated. Using a model of post-surgical tumor immunity, we show that in vivo depletion of CD62L-expressing cells before or immediately after surgical tumor resection enabled the development of anti-tumor concomitant responses against poorly immunogenic B16 (melanoma) or MTE-Ras (head &amp; neck cancer) tumor cells. Anti-CD62L mAb administration depleted the cellular immune components that express CD62L, including NK, NKT, Mo, Ma, B, and T cells. Within the T cell compartment, naïve T cells (CD44lo CD62Lhi), effector (CD44hi CD62Llo), memory (CD44hi CD62Lhi) and regulatory T cells (Treg, CD4 CD25 Foxp3) were also depleted, while effector CD62L-negative T cells were spared in the TDLN. Tumor immunity did not occur in the absence of a primary tumor (sham surgery group) or after CD8 depletion. Whereas anti-CTLA-4 or anti-PD-1 mAbs failed as monotherapies, their administration during CD62L depletion restored their anti-tumor properties. The unified global gene expression analysis of the TDLN shows the significant enrichment of biological processes involved in the CD8 T cell effector phase, IL-2/IL-15, TNF-α, IFN-γ, IFN-α, IL-6, responses, mitotic cell division, glycolysis, and acetylation. Also, genes related to Treg responses were downregulated. These data point to a process in which depletion of CD62L cells in tumor-bearing hosts transforms the TDLN into a highly active immunological site in which tumor-reactive effector CD8 T cells (CD62L-negative) actively divide in the absence of Treg, accompanied by a cytokine response, glucose consumption, and acetylation of transcriptional factors and histones. These results identify an unrecognized role of CD62L-expressing cells in regulating concomitant anti-tumor immunity and restoring anti-tumor responses by checkpoint blockade inhibitors. Our study provides a new framework that could help understand how anti-tumor responses are limited. Citation Format: Brianna Burke, Lourdes Plaza-Rojas, Cynthia Perez, Elena Kostenko, Anna Austin, Justin Boucher, Kushal Prajapati, Michael Delos Reyes, Christine Chung, Jose-Alejandro Guevara-Patino. Concomitant anti-tumor immunity and checkpoint blockade responses are restored by depletion of CD62L expressing cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6414.
Abstract 1953: Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort
Authors: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki
Journal: Cancer Research (2023)

Abstract Introduction: It is unknown how much of the increased all-cause mortality risk in Black individuals who ever-smoked is due to race as a social construct versus biological factors such as genetic ancestry. We examined the association of genetic ancestry with all-cause mortality, controlling for risk factors and self-reported race/ethnicity, in the PLCO cohort. Methods: We used PLCO data from 52,708 White individuals who ever-smoked (18281 deaths) and 2,585 Black individuals who ever-smoked (1108 deaths). Genetic ancestry was determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. We fit Cox models for time to death, controlling for smoking history and other risk factors. Results: Self-reported Black individuals who ever-smoked had increased all-cause mortality versus self-reported White individuals who ever-smoked (HR=1.14, 95%CI: 1.07-1.22, p=0.00007). For White individuals, increases in European ancestry were associated with increased death risk, (HR=1.009 per 1% increase in European ancestry, 95%CI:1.003-1.015, p=0.002). HRs for European ancestry, by quartile, were 1.040, 1.061 and 1.063, with the last two HRs demonstrating statistical significance (95%CI:1.0018-1.106, p = 0.005, and 95%CI:1.020-1.108, p=0.004), respectively. For Black individuals, increases in African ancestry were associated with increased death risk, (HR=1.003 per 1% increase in African ancestry, 95%CI: 0.998-1.008, p=0.214), although not statistically significant. HRs for African ancestry, by quartile, were 1, 1.16, 1.14, and 1.21, with the last HR demonstrating statistical significance (95%CI:1.010-1.450, p = 0.03). Conclusions: For self-reported White individuals who ever-smoked, increasing European ancestry was associated with an increased all-cause mortality risk. For self-reported Black individuals who ever-smoked, there was suggestive evidence that increasing African ancestry may increase all-cause mortality risk. However, associations with ancestry were small and may be vulnerable to residual confounding. Impact/Significance: A mechanistic explanation for this finding is unclear, but it could be related to population genetic “fitness” with reduced genetic admixture leading to decreased fitness for survival. Citation Format: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li C. Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association between genetic ancestry and all-cause mortality among Black and White ever-smokers in the PLCO cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1953.
Abstract 474: Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer
Authors: Jinping Wu, Ke An, Douglas D. Fang, Jianyu Lu, Lihong Hu, Jing Wang, Kaili Zhang, Yuanfeng Xia, Charles Ding, Shuhui Chen, Sha Wei
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) has recently surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Approximately 70% of BC was ER+, in which estrogen receptor α (ERα, encoded by ESR1 gene) drives dysregulated cell proliferation. In clinic, ER+ BC has been effectively treated by endocrine therapy targeting estrogen or ER. As the first approved ERα degrader, fulvestrant has proven to be effective for locally advanced or metastatic BC. However, its clinical utilization is hampered by inconvenience of intramuscular injection, as well as its poor PK/PD profile and limited efficacy, especially in the patient population that developed ESR1 mutation-conferring drug resistance after the earlier line of treatment with an aromatase inhibitor. Thus, developing an oral and more effective therapy for ER+ BC remains an unmet medical need. We report herein discovery and preclinical investigation of a novel orally bioavailable SERD TFX06. TFX06 demonstrated potent binding affinity to ERα with a Ki of 0.10 nM and preferably antagonized ERα to ERβ with an IC50 value of 0.086 nM and 2.83 nM, respectively. TFX06 potently induced ERα degradation in ER+ BC cells and substantially inhibited cell proliferation in BC cell lines with ER wild type (WT), and MCF-7 cells expressing Y537S or D538G mutants. Oral administration of TFX06 demonstrated impressive antitumor efficacy in ER WT (TGI = 101%) and ER D538G-expressing (TGI = 99%) MCF-7 cell line-derived xenograft (CDX) models in mice. Similarly, in an ER+ BC patient-derived xenograft (PDX) model (HCI-013) with ER Y537S mutation, TFX06 also exerted excellent antitumor activity (TGI = 99%). Furthermore, TFX06 in combination with palbociclib achieved synergistic activity in MCF-7 CDX model. Moreover, TFX06 exhibited an excellent correlation between systemic/local drug exposure, pharmacodynamic modulation (i.e., ERα downregulation) and antitumor activity. Collectively, these findings demonstrate that TFX06 is a novel, orally bioavailable SERD. TFX06 demonstrates substantial antitumor activity in both in vitro and in vivo preclinical tumor models, including those expressing ESR1 mutations, through downregulation of ERα. The preclinical data warranted the clinical evaluation of TFX06 in human with an IND application submitted to the China NPMA. Citation Format: Jinping Wu, Ke An, Douglas D. Fang, Jianyu Lu, Lihong Hu, Jing Wang, Kaili Zhang, Yuanfeng Xia, Charles Ding, Shuhui Chen, Sha Wei. Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 474.
Abstract 5884: Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model
Authors: Mitchell Martin, Michael J. Crowley, Geoffrey Markowitz, Alain Borczuk, Chen Zhang, Liron Yoffe, Arshdeep Singh, Nasser K. Altorki, Vivek Mittal
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer is the leading cause of cancer-related death in the US and worldwide, with a 5-year survival of ~18-20%. Understanding of the biology of early lung cancer is necessary to intercept early steps of progression. Indeed, increased utility of low-dose CT guided lung cancer screens in populations at risk have begun to detect early premalignant disease; however, little is known about the underlying biology that drives progression of preinvasive lesions to invasive adenocarcinoma. Moreover, there exists a lack of reliable animal models to assess interception strategies to target disease progression. We have developed and characterized a lung cancer cell-of-origin-specific KRAS-driven mouse model which accurately mirrors progression of human precursor lesions to invasive disease. Transcriptional analysis of preinvasive and invasive stages identified cellular and molecular alternations observed in human lesions, including upregulation of cell proliferation, extracellular matrix remodeling, and an increasingly complex immune microenvironment. Interrogation with immunofluorescence microscopy and Hyperion mass cytometry imaging showed marked reprogramming of the immune microenvironment including increased T cell infiltration and abundance of T regulatory cells (Tregs). Surprisingly, depletion of T cells impaired progression of preinvasive lesions, implicating the critical immunosuppressive roles of Tregs. Spatial transcriptomics (10X Genomics Visium) revealed unique spatial transcriptional changes in the progression from preinvasive to invasive stage disease, including specific ligand-receptor interactions highly expressed in Tregs. Genetic and pharmacological approaches using FoxP3-DTR-GFP mice and low dose cyclophosphamide have begun to define the functional role of Tregs in early premalignant disease. This study demonstrates critical roles of immunosuppressive Tregs in driving progression of preinvasive to invasive lung cancer, and advocates for Treg targeting as a potent immunoprevention approach for patients at risk of developing lung cancer. Citation Format: Mitchell Martin, Michael J. Crowley, Geoffrey Markowitz, Alain Borczuk, Chen Zhang, Liron Yoffe, Arshdeep Singh, Nasser K. Altorki, Vivek Mittal. Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5884.
Abstract 5659: Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins
Authors: Mikkel K.M. Aasted, Aaron C. Groen, John T. Keane, Sally Dabelsteen, Edwin Tan, Julia Schnabel, Fang Liu, Hyeon-Gyu S. Lewis, Constantine Theodoropulos, Avery D. Posey, Hans H. Wandall
Journal: Cancer Research (2023)

Abstract The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens also found in healthy tissues. Such targets often do not display sufficient cancer selectivity to be used for potent antibody based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in the expression of tumor-associated carbohydrate antigens that are not present on healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumours, but only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and through a glycopeptide immunization strategy developed a cancer-specific monoclonal antibody, 4C8. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer selective by immunohistochemistry of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression, and increased survival in vivo. Importantly, 4C8 CAR T cells selectively killed target cells in a mixed organotypic skin cancer model without affecting healthy CD44v6+ keratinocytes, indicating tolerability and safety. Targeting aberrantly glycosylated glycopeptide epitopes may provide the cancer selectivity needed for solid tumour immunotherapy. Citation Format: Mikkel K.M. Aasted, Aaron C. Groen, John T. Keane, Sally Dabelsteen, Edwin Tan, Julia Schnabel, Fang Liu, Hyeon-Gyu S. Lewis, Constantine Theodoropulos, Avery D. Posey, Hans H. Wandall. Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrant O-glycosylated proteins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5659.